title: Cystic fibrosis transmembrane conductance regulator degradation: cross-talk between the ubiquitylation and SUMOylation pathways.
abstract: Defining the significant checkpoints in cystic fibrosis transmembrane conductance regulator (CFTR) biogenesis should identify targets for therapeutic intervention with CFTR folding mutants such as F508del. Although the role of ubiquitylation and the ubiquitin proteasome system is well established in the degradation of this common CFTR mutant, the part played by SUMOylation is a novel aspect of CFTR biogenesis/quality control. We identified this post-translational modification of CFTR as resulting from its interaction with small heat shock proteins (Hsps), which were found to selectively facilitate the degradation of F508del through a physical interaction with the SUMO (small ubiquitin-like modifier) E2 enzyme, Ubc9. Hsp27 promoted the SUMOylation of mutant CFTR by the SUMO-2 paralogue, which can form poly-chains. Poly-SUMO chains are then recognized by the SUMO-targeted ubiquitin ligase, RNF4, which elicited F508del degradation in a Hsp27-dependent manner. This work identifies a sequential connection between the SUMO and ubiquitin modifications of the CFTR mutant: Hsp27-mediated SUMO-2 modification, followed by ubiquitylation via RNF4 and degradation of the mutant via the proteasome. Other examples of the intricate cross-talk between the SUMO and ubiquitin pathways are discussed with reference to other substrates; many of these are competitive and lead to different outcomes. It is reasonable to anticipate that further research on SUMO-ubiquitin pathway interactions will identify additional layers of complexity in the process of CFTR biogenesis and quality control.
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, PA 15224, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Ahner
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Gong
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Frizzell
mesh_terms: D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D018832:Molecular Chaperones; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D015398:Signal Transduction; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: C505032:CFTR protein, human; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C114070:RNF4 protein, human; D014157:Transcription Factors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: Hsp27; STUbL; cystic fibrosis transmembrane conductance regulator; degradation; endoplasmic reticulum associated; proteasome; quality control; small heat shock proteins; small ubiquitin-like modifier; ubiquitin